The etiologies of primary demyelinating diseases such as multiple sclerosis (MS) are unknown. One testable hypothesis is that destruction of myelin and oligodendrocyte results from an immune attack directed against antigen triggered by virus infection. We have used infection to mice with Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, to study the role of the immune response in demyelination and in neurologic disease. The long term goal of these experiments is to reveal the immune mechanisms of demyelination and neurologic disease with the hope that this will provide new insights into the treatment of MS. There are two major specific aims in the proposed experiments. First, in order to determine which viral genes are involved in inducing a protective immune response and which genes are targeted in the pathogenic phase of demyelinating disease, we have divided the TMEV genome into three regions so that they can be expressed individually in target cells in vitro and as transgenes in vivo. Fibroblasts transfected with the TMEV coding blocks will be used to determine the location of the genes recognized by T cells appearing early during the protective host response to viral infection and late during the pathogenic phase of disease. The same coding blocks expressed as transgenes in resistant and susceptible strains will presumably induce tolerance to sets of viral antigens, permitting to assess the significance of immune recognition of these antigens in resistance to viral infection and in the pathogenesis of demyelination. In the second specific aim we will utilize beta2- macroglobulin deficient (-/-) mice which when infected with TMEV develop prominent demyelination but no neurologic deficits. These experiments have direct relevance to MS, in which frequently there is a discrepancy between demyelination provides a unique opportunity to dissect those components of the immune response important in demyelination versus those important in neurologic deficits. We will first determine the nature of the immune response (CTL, Th1, and Th2) in CNS of infected Beta-2m (+/+) and Beta-2m (-/-) of susceptible and resistant haplotypes. We will then take advantage of the Beta2-m (-/-) model to establish the immunologic basis of neuronal injury in the demyelinated host. Using a new technique in the mouse to measure motor and sensory spinal cord conduction in vivo, we will determine those components of the immune response responsible for neurophysiologic abnormalities. These experiments have the potential to elucidate new strategies for the treatment of human CNS demyelinating disorders.